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The objective was to determine if antigen-specific tissue resident memory T (TRM) cells persist in respiratory tissues of adults immunized as children with whole cell pertussis (wP) or acellular pertussis (aP) vaccines. Mononuclear cells from tonsil or nasal tissue cells were cultured with Bordetella pertussis antigens and TRM cells quantified by flow cytometry. Adults immunized with wP vaccines as children had significantly more IL-17A and IFN-y-producing TRM cells that respond to B. pertussis antigens in respiratory tissues when compared with aP-primed donors. Our findings demonstrate that wP vaccines induce CD4 TRM cells that can persist in respiratory tissues for decades.
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As a pleiotropic cytokine consisting of IL-12p35 and IL-12p40, Interleukin-12 (IL-12) features in inflammation regulation and anti-bacterial immunity. While IL-12 homologs have been identified in non-mammalian species, the precise mechanisms by which IL-12 contributes to early adaptive immune responses in vertebrates remain incompletely understood. Herein, an evolutionary conserved Oreochromis niloticus IL-12 (defined as OnIL-12) was identified by synteny characterization, structural comparisons and phylogenetic pattern of IL-12p35b and IL-12p40a. IL-12p35b and IL-12p40a exhibited widespread expression in lymphoid-related tissues of tilapia, while their mRNA expression in head-kidney demonstrated a significant increase after Edwardsiella piscicida infection. Compared with other lymphocytes, recombinant OnIL-12 (rOnIL-12) displayed stronger affinity binding to T cells. Although stimulation of lymphocytes with the p35b or p40a subunit resulted in a significant induction of IFN-γ expression, rOnIL-12 showed stronger potential to promote IFN-γ expression than these subunits. rOnIL-12 not only elevated the mRNA expression level Th1 cell-associated transcription factor T-bet in lymphocytes, but also increased the proportion of CD4-1+IFN-γ+ lymphocytes. Moreover, the mRNA and phosphorylation levels of STAT1, STAT3, STAT4 and STAT5 were enhanced by rOnIL-12. These findings will offer previous evidence for further exploration into the regulatory mechanisms of Th1 cellular immunity in early vertebrates.
Assuntos
Ciclídeos , Interleucina-12 , Animais , Interleucina-12/genética , Células Th1 , Ciclídeos/genética , Ciclídeos/metabolismo , Filogenia , Interferon gama/genética , Interferon gama/metabolismo , RNA Mensageiro/metabolismoRESUMO
Interferon gamma (IFN-γ), the member of type II interferons, is a major driver and effector cytokine for Th1 cells and plays broad roles in regulating the function of immune cells. Teleost fish represents the oldest living bony vertebrates containing T-lymphocyte subsets. However, whether or how the regulatory mechanisms of IFN-γ on Th1 cells occur in teleost fish remain unknown. In this study, full-length transcriptome sequencing was performed to analyze the differentially expressed genes (DEGs) and signaling pathways in the IFN-γ stimulated lymphocytes of flounder (Paralichthys olivaceus), the data showed 811 genes were upregulated and 1107 genes were downregulated, Th1 and Th2 cell differentiation pathway was remarkably enriched from DEGs, and the genes in the Th1 cell differentiation pathway were upregulated and verified. Accordingly, variations on Th1 cell differentiation marker genes and CD4+ cells were investigated after IFN-γ stimulation, the results confirmed that CD4+ T lymphocytes proliferated significantly after IFN-γ stimulation, accompanied by eight genes significant upregulation and increased T-bet expression in lymphocytes. In conclusion, the results revealed an induction of IFN-γ on Th1-type immune response, providing novel perspectives into the differentiation of CD4+ T lymphocytes in teleost.
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Linguado , Interferon gama , Animais , Interferon gama/genética , Transcriptoma , Linfócitos T CD4-Positivos , Células Th1 , ImunidadeRESUMO
OBJECTIVES: The differentiation of CD4+ T cells is regulated by a complex and fine signaling pathway composed of many molecules during immune response, and the molecular mechanism for regulating T-bet expression is unclear. Mediator complex subunit 1 (Med1) can combine with a variety of co-factors to regulate gene transcription, promote cell proliferation and survival, and affect invariant natural killer T cell (iNKT) development. This study aims to investigate the effect of Med1 on T cell development and CD4+ T cell differentiation in immune response. METHODS: Mice with T cell-specific knockout of Med1 gene (Med1F/FCD4cre+, KO) were constructed and verified. The percentage and number of CD4+ and CD8+ T cells in thymus, spleen, and lymph nodes of KO mice and control (Con) mice (Med1F/FCD4cre-) were detected by flow cytometry. After 8 days of infection with lymphocytic choriomeningitis virus (LCMV), the percentage and number of CD4+ T cells or antigen-specific (GP66+) CD4+ T cells, the percentage and number of Th1 cells (Ly6c+PSGL1+) in CD4+ T cells or antigen-specific CD4+ T cells were examined in the spleen of mice. Moreover, the fluorescence intensity of T-bet in CD4+ T cells or antigen-specific CD4+ T cells was analyzed. RESULTS: Compared with the Con group, the percentage and number of CD4+ T cells and CD8+ T cells in the thymus, CD4+ T cells in the spleen and lymph nodes of the KO group showed no significant differences (all P>0.05), but the percentage and number of CD8+ T cells in the spleen and lymph nodes of the KO group were diminished significantly (all P<0.05). After 8 days of infection with LCMV, there was no significant difference in the percentage and number of CD4+ T cells or antigen-specific CD4+ T cells in the spleen between the KO group and the Con group (all P>0.05), while in comparison with the Con group, the percentage and number of Th1 cells in CD4+ T cells or antigen-specific CD4+ T cells, and the expression of T-bet in CD4+ T cells or antigen-specific CD4+ T cells were significantly reduced in the spleen of the KO group (all P<0.05). CONCLUSIONS: Specific knockout of Med1 in T cells does not affect the development of CD4+ and CD8+ T cells in the thymus, but does affect the maintenance of peripheral CD8+ T cells. In the immune response, Med1 gene deletion affects the expression of transcription factor T-bet, which in turn to reduce Th1 cell differentiation.
Assuntos
Linfócitos T CD8-Positivos , Subunidade 1 do Complexo Mediador , Camundongos , Animais , Linfócitos T CD8-Positivos/metabolismo , Subunidade 1 do Complexo Mediador/metabolismo , Imunidade , Diferenciação Celular , Vírus da Coriomeningite Linfocítica/metabolismo , Células Th1/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Conivaptan, a nonselective antagonist of vasopressin receptors V1a and V2, is the first drug of this class to be used for treating euvolemic and hypervolemic hyponatremia. Recently, increasing evidence supports the involvement of vasopressin in immune responses. AIMS: In this study, we investigated the effect of conivaptan on the modulation of CD4+ T cell homeostasis and the progression of experimental colitis. METHODS: The expression of the V1a receptor on CD4+ T cells was detected by immunofluorescence and western blot. The subset of isolated CD4+ T cells were examined after arginine vasopressin (AVP) incubation. CD4+ T cells were injected into DNBS-induced mice through the tail vein. The severity of colitis was evaluated according to weight, disease activity index (DAI), and morphological injury. Intracellular Ca2+ ([Ca2+]i) signaling in CD4+ T cells was measured using the Fluo-3 AM loading method. T-bet and IFN-γ mRNAs in the colon were detected by real-time polymerase chain reaction (qPCR). RESULTS: We found that CD4+ T cells expressed the V1a receptor. Activation of the V1a receptor significantly promoted the differentiation of CD4+ T cells into T helper 1 (Th1) cells. This process was blocked by conivaptan treatment. However, the activation of the V1a receptor did not evoke an increase in [Ca2+]i in CD4+ T cells. Notably, conivaptan markedly alleviated body weight loss, pathological damage, and expression of T-bet and IFN-γ in the colon of DNBS-treated mice. CONCLUSIONS: For the first time, we report that conivaptan attenuated colitis by inhibiting the differentiation of CD4+ T cells into Th1 cells. Mechanistically, the anti-inflammatory role of conivaptan is independent of [Ca2+]i.
Assuntos
Colite Ulcerativa , Colite , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Camundongos , Células Th1RESUMO
BACKGROUND: Insulitis is defined by the presence of immune cells infiltrating in the pancreatic islets that might progress into the complete ß-cell loss. The immunomodulatory properties of bone marrow-derived mesenchymal stem cells (BM-MSCs) have attracted much attention. This study aimed to evaluate the possible immunomodulatory effects of rat BM-MSCs and MSCs-derived insulin-producing cells (IPCs) in a mouse model of pancreatic insulitis. METHODS: Insulitis was induced in BALB/c mice using five consecutive doses of streptozotocin. MSCs or IPCs were directly injected into the pancreas of mice and their effects on the expression of Th subsets-related genes were evaluated. RESULTS: Both BM-MSCs and IPCs significantly reduced the expression of pancreatic Th1-related IFN-γ (P < 0.001 and P < 0.05, respectively) and T-bet genes (both P < 0.001). Moreover, the expression of IL-10 gene was significantly increased in IPC-treated compared to BM-MSC- or PBS-treated mice (P < 0.001 both comparisons). CONCLUSIONS: BM-MSCs and IPCs could successfully suppress pathologic Th1 immune responses in the mouse model of insulitis. However, the marked increase in IL-10 gene expression by IPCs compared to BM-MSCs suggests that their simultaneous use at the initial phase of autoimmune diabetes might be a better option to reduce inflammation but these results need to be verified by further experiments.
Assuntos
Interleucina-10 , Pâncreas , Animais , Diferenciação Celular , Modelos Animais de Doenças , Imunidade , Insulina , Interleucina-10/genética , Camundongos , Camundongos Endogâmicos BALB C , Ratos , EstreptozocinaRESUMO
Acquisition of effector functions in T cells is guided by transcription factors, including NF-κB, that itself is tightly controlled by inhibitory proteins. The atypical NF-κB inhibitor, IκBNS, is involved in the development of Th1, Th17, and regulatory T (Treg) cells. However, it remained unclear to which extend IκBNS contributed to the acquisition of effector function in T cells specifically responding to a pathogen during in vivo infection. Tracking of adoptively transferred T cells in Listeria monocytogenes infected mice antigen-specific activation of CD4+ T cells following in vivo pathogen encounter to strongly rely on IκBNS . While IκBNS was largely dispensable for the acquisition of cytotoxic effector function in CD8+ T cells, IκBNS -deficient Th1 effector cells exhibited significantly reduced proliferation, marked changes in the pattern of activation marker expression, and reduced production of the Th1-cell cytokines IFN-γ, IL-2, and TNF-α. Complementary in vitro analyses using cells from novel reporter and inducible knockout mice revealed that IκBNS predominantly affects the early phase of Th1-cell differentiation while its function in terminally differentiated cells appears to be negligible. Our data suggest IκBNS as a potential target to modulate specifically CD4+ T-cell responses.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Proteínas I-kappa B/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Células Th1/imunologia , Transferência Adotiva/métodos , Animais , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/fisiologia , Citocinas/imunologia , Interferon gama/imunologia , Interleucina-2/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts due to enhanced platelet clearance and compromised production. Traditionally, ITP was regarded a B cell mediated disorder as anti-platelet antibodies are detected in most patients. The very nature of self-antigens, evident processes of isotype switching and the affinity maturation of anti-platelet antibodies indicate that B cells in order to mount anti-platelet immune response require assistance of auto-reactive CD4+ T cells. For a long time, ITP pathogenesis has been exclusively reviewed through the prism of the disturbed balance between Th1 and Th2 subsets of CD4+ T cells, however, more recently new subsets of these cells have been described including Th17, Th9, Th22, T follicular helper and regulatory T cells. In this paper, we review the current understanding of the role and immunological mechanisms by which CD4+ T cells contribute to the pathogenesis of ITP.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Púrpura Trombocitopênica Idiopática/imunologia , Subpopulações de Linfócitos T/imunologia , Humanos , FenótipoRESUMO
Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammatory infiltration and demyelination in the central nervous system (CNS). Among the factors involved in the immunological mechanisms of MS, T helper 1 (Th1) cells and T helper 17 (Th17) cells play a critical role. Compound 21, a novel phloroglucinol derivative, significantly protected myelin from damage in our previous study. However, it remains unclear whether this compound affects MS. In this study, the experimental autoimmune encephalomyelitis (EAE) rat model was established to mimic the pathological process of MS and evaluate the neuroprotective effect of Compound 21. The results illustrated that Compound 21 treatment notably attenuates neurological deficits, immune infiltration, and demyelination in EAE rats. Our mechanistic investigation revealed that Compound 21 treatment reduces the population of Th1/Th17 cells and inhibits their infiltration into the CNS. Furthermore, we found that the inhibition of Th1/Th17 cell infiltration is related to the direct suppression of Th1/Th17 cell differentiation and the inhibition of proinflammatory microglial cells. Collectively, these results confirm that Compound 21 suppresses infiltrated Th1/Th17 cells to alleviate demyelination in EAE rats, suggesting its potential role as a novel candidate for MS treatment.
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Encefalomielite Autoimune Experimental , Células Th17 , Animais , Diferenciação Celular , Encefalomielite Autoimune Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Floroglucinol/farmacologia , Ratos , Células Th1RESUMO
Paeoniflorin shows distinct anti-arthritis and immunoregulatory activities, but its rather low bioavailability via oral administration greatly challenges its known mechanism of in vivo activity. Our data showed that oral administration, instead of intraperitoneal injection, of paeoniflorin significantly reduced the polyarthritis index by 44.4%, reduced paw swelling by 18.4% and delayed the onset of arthritis in collagen-induced arthritis (CIA) mice. Oral paeoniflorin treatment also downregulated the systemic pro-inflammatory cytokines IL-6 (by 52.2%), TNF-α (by 57.7%) and IL-1ß (by 34.1%). A pharmacokinetic study revealed that the maximal plasma concentration of paeoniflorin after oral administration was 4.8 ± 1.9 µM in the CIA mice, much lower than the effective concentration in vitro (30 µM). In contrast, paeoniflorin was highly concentrated in the gut content, intestine and Peyer's patches. T cell analysis showed that paeoniflorin markedly reduced transcription factors of Th1 and Th17, inhibited Th1 by 22.2% and 23.1% and Th17 by 43.2% and 25.4% (p < 0.05) in the mesenteric lymph node and Peyer's patches, respectively. Paeoniflorin did not have a significant impact on Th1 and Th17 in the spleen. For the first time, these data suggest that paeoniflorin accumulates in the intestine and primarily modulates Th1 and Th17 responses in the mesenteric lymph nodes and Peyer's patches, rather than in the spleen, to exert anti-arthritis effects.
Assuntos
Artrite Experimental/tratamento farmacológico , Glucosídeos/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Linfonodos/efeitos dos fármacos , Monoterpenos/farmacologia , Nódulos Linfáticos Agregados/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Citocinas/biossíntese , Glucosídeos/farmacocinética , Glucosídeos/uso terapêutico , Mucosa Intestinal/imunologia , Linfonodos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Monoterpenos/farmacocinética , Monoterpenos/uso terapêutico , Nódulos Linfáticos Agregados/imunologia , Células Th1/imunologia , Células Th17/imunologiaRESUMO
OBJECTIVE: The objective of this study is to investigate the role of cathepsin H (CatH), a lysosomal cysteine protease, in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. METHODS: EAE was induced in CatH-deficient mice (CatH-/-) and wild-type littermates (+/+) using myelin oligodendrocyte glycoprotein (MOG) 35-55. The effects of CatH deficiency were determined by clinical scoring, mRNA expression levels of Tbx21, Rorc and FoxP3, protein levels of poly(I:C)-induced toll-like receptor 3 (TLR3) and phosphorylation of IRF3, and secretion of interferon-ß (IFN-ß) by splenocytes. RESULTS AND CONCLUSIONS: CatH-/- showed a significantly earlier disease onset of EAE and increased Th1 cell differentiation in splenocytes. Splenocytes prepared from immunized CatH-/- showed a significant decrease in poly(I:C)-induced increased TLR3 expression, interferon regulatory factor 3 (IRF3) phospholylation and IFN-ß secretion. Therefore, CatH deficiency impaired TLR3-mediated activation of IRF3 and consequent secretion of IFN-ß from dendritic cells, leading to the enhancement of Th1 cell differentiation and consequent early disease onset of EAE.
Assuntos
Catepsina H/deficiência , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Ativação de Macrófagos/genética , Células Th1 , Receptor 3 Toll-Like/genética , Animais , Catepsina H/genética , Diferenciação Celular/genética , Fator Regulador 3 de Interferon/biossíntese , Fator Regulador 3 de Interferon/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito/genética , Fragmentos de Peptídeos/genética , Transdução de Sinais/genética , Baço/citologiaRESUMO
BACKGROUND: Chronic hepatitis B (CHB) is one of the major infectious diseases in which CD4+ T helper (Th) cells play a crucial role. Th9 cells are a distinct subset of CD4+ Th cells with important physiological functions. OBJECTIVE: The study aimed to assess the potential involvement of Th9 cells in the inadequate immune response leading to chronic HBV infection. PATIENTS AND METHODS: Peripheral blood samples were collected from 22 CHB patients and 16 healthy controls (HC). The frequencies of circulating Th9, Tc9, Th1, and Tc1 cells were determined by flow cytometry. Serum levels of IL-9 and IL-10 were analyzed by ELISA. Serum biochemical indices of liver function were measured using an automated analyzers. Serum HBV DNA loads were analyzed by real-time PCR. The potential association of the frequency of Th9, Tc9, Th1 or Tc1 cells with clinical parameters was assessed. RESULTS: The frequency of circulating Th9 cells was significantly lower in CHB patients than those in HC. However, no significant differences in the frequency of Tc9, Th1 or Tc1 cells were observed between the two groups. The percentages of Th9 cells, but not Tc9 cells, were negatively correlated with HBV DNA loads, whereas the percentages of Tc1 cells were positively correlated with viral loads in CHB patients. Moreover, there was a positive correlation between serum levels of IL-9 and IL-10 and HBV DNA loads in patients with chronic HBV infection. CONCLUSION: The depletion of Th9 cells is associated with the development of chronic HBV infection.
Assuntos
Hepatite B Crônica/epidemiologia , Hepatite B Crônica/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Estudos de Casos e Controles , DNA Viral/sangue , Feminino , Citometria de Fluxo , Humanos , Interleucina-10/sangue , Interleucina-9/sangue , Masculino , Pessoa de Meia-Idade , Carga ViralRESUMO
During infection, the release of damage-associated molecular patterns, so-called "alarmins," orchestrates the immune response. The alarmin IL-33 plays a role in a wide range of pathologies. Upon release, IL-33 signals through its receptor ST2, which reportedly is expressed only on CD4(+) T cells of the Th2 and regulatory subsets. Here we show that Th1 effector cells also express ST2 upon differentiation in vitro and in vivo during lymphocytic choriomeningitis virus (LCMV) infection. The expression of ST2 on Th1 cells was transient, in contrast to constitutive ST2 expression on Th2 cells, and marked highly activated effector cells. ST2 expression on virus-specific Th1 cells depended on the Th1-associated transcription factors T-bet and STAT4. ST2 deficiency resulted in a T-cell-intrinsic impairment of LCMV-specific Th1 effector responses in both mixed bone marrow-chimeric mice and adoptive cell transfer experiments. ST2-deficient virus-specific CD4(+) T cells showed impaired expansion, Th1 effector differentiation, and antiviral cytokine production. Consequently, these cells mediated little virus-induced immunopathology. Thus, IL-33 acts as a critical and direct cofactor to drive antiviral Th1 effector cell activation, with implications for vaccination strategies and immunotherapeutic approaches.
Assuntos
Infecções por Arenaviridae/imunologia , Regulação da Expressão Gênica , Interleucinas/imunologia , Fator de Transcrição STAT4/metabolismo , Proteínas com Domínio T/metabolismo , Células Th1/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Separação Celular , Citometria de Fluxo , Perfilação da Expressão Gênica , Receptores de Hialuronatos/metabolismo , Interferon gama/metabolismo , Interleucina-33 , Selectina L/metabolismo , Vírus da Coriomeningite Linfocítica , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/citologia , Células Th1/citologiaRESUMO
A flavonoid Astragalin (kaempferol-3-O-ß-d-glucopyranoside, Ast) has several biological activities including anti-oxidant, anti-HIV, and anti-allergic effects. Nonetheless, its insolubility in hydrophilic solvents imposes restrictions on its therapeutic applications. In this study, we investigated the effects of water-soluble astragalin-galactoside (kaempferol-3-O-ß-d-isomaltotrioside, Ast-Gal) on murine bone marrow-derived dendritic cell (DC) maturation and T helper (Th) cell-mediated immune responses. Ast-Gal significantly increased maturation and activation of DCs through the upregulation of surface markers, such as cluster of differentiation (CD)80, CD86, and Major histocompatibility complex (MHC) II in a dose-dependent manner, while Ast had little effects. Additionally, Ast-Gal-treated DCs markedly secreted immune-stimulating cytokines such as interleukin (IL)-1ß, IL-6, and IL-12. Importantly, Ast-Gal strongly increased expression of IL-12, a polarizing cytokine of Th1 cells. In a co-culture system of DCs and CD4⺠T cells, Ast-Gal-treated DCs preferentially differentiates naïve CD4⺠T cells into Th1 cells. The addition of neutralizing IL-12 monoclonal antibody (mAb) to cultures of Ast-Gal-treated DCs and CD4⺠T cells significantly decreased interferon (IFN)-γ production, thereby indicating that Ast-Gal-stimulated DCs enhance the Th1 response through IL-12 production by DCs. Injection with Ast-Gal-treated DCs in mice increased IFN-γ-secreting Th1 cell population. Collectively, these findings indicate that hydrophilically modified astragalin can enhance Th1-mediated immune responses via DCs and point to a possible application of water-soluble astragalin-galactoside as an immune adjuvant.
Assuntos
Células Dendríticas/imunologia , Galactosídeos/farmacologia , Imunidade/efeitos dos fármacos , Quempferóis/farmacologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Animais , Apresentação de Antígeno/imunologia , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Biomarcadores , Citocinas/genética , Citocinas/metabolismo , Células Dendríticas/metabolismo , Expressão Gênica , Imunofenotipagem , Camundongos , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th1/metabolismoRESUMO
We report the case of a 59-year-old woman who simultaneously suffered from psoriasis and vitiligo. The depigmented areas were predominantly but not exclusively limited to current or former psoriatic plaques. These two diseases share many common features, e. g., both are Tcell-mediated autoimmune diseases in which the Koebner phenomenon occurs. However, it is still not known whether the coincidence is random or significant. Prospective clinical and epidemiological research will hopefully reveal the association soon.
Assuntos
Doenças Autoimunes , Psoríase , Vitiligo , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Psoríase/complicações , Psoríase/diagnóstico , Linfócitos T , Vitiligo/complicações , Vitiligo/diagnósticoRESUMO
Rapamycin is a new immunosuppressant that has a primarily anti-inflammatory effect and selectively inhibits the activation of T helper (Th)-cell subsets. It is widely used to treat autoimmune disease. We studied the mechanism of rapamycin action against experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, a classic animal model of multiple sclerosis. Rapamycin significantly inhibited the development of EAE by decreasing both clinical scores and inflammatory cell infiltration into the spinal cord. Furthermore, rapamycin reversed EAE symptoms in mice showing the initial signs of paralysis. Rapamycin, is a mammalian target of rapamycin (mTOR) inhibitor. By measuring the downstream markers phospho-mTOR (p-mTOR)/mTOR and phospho-signal transducer and activator of transcription 3 (p-STAT3)/STAT3, we showed that rapamycin suppressed the mTOR-STAT3 pathway in EAE mice. The mTOR-STAT3 signaling pathway is important for Th1 and Th17 cell responses. We found that rapamycin-treated mice had reduced proportions of Th1 and Th17 cells, as well as lower mRNA expression for the transcription factors T-bet and RoRγt in EAE mouse splenocytes. To evaluate Th1 and Th17 cell function, we examined expression of their specific cytokines in the peripheral immune system and central nervous system. Rapamycin treatment reduced protein and mRNA levels of interferon (IFN)-γand interleukin (IL)-17 in splenocytes, and reduced IFN-γ and IL-17 mRNA levels in the spinal cords of EAE mice. These findings suggest that rapamycin treatment inhibits the mTOR-STAT3 pathway in EAE mice, thereby promoting immunosuppression. This study may provide new insight into the mechanism controlling rapamycin effects in multiple sclerosis.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Sirolimo/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Citocinas/metabolismo , Feminino , Interferon gama/farmacologia , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Glicoproteína Mielina-Oligodendrócito/metabolismo , Fator de Transcrição STAT3/efeitos dos fármacos , Serina-Treonina Quinases TOR/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismoRESUMO
The mechanism of anti-tumor effect of transarterial Immuno-Embolization (TIE) using OK-432 has not been well elucidated. In this study, we aimed to investigate the tissue injury and immune response after portal venous embolization (PVE) with/without OK-432. Embolic materials (L group: lipiodol, LF group: lipiodol+fibrinogen, LO group: lipiodol+OK-432, LFO group: lipiodol+fibrinogen+OK-432) were administered via the right portal vein in Wistar rats. The histological findings in LFO group demonstrated liver damage with severe architectural changes. The concentrations of CD68(+) cells were observed in a time-dependent manner; it was significantly increased in the LO group on day 1 and in the LFO group on day 3. CD68(+)CD163(-) macrophages significantly increased in the LFO group on day 7 (P<0.05). In conclusion, PVE with fibrinogen and OK-432 markedly increased the CD68(+)CD163(-) infiltrating macrophages around the peri-portal area in the liver. This novel technique could be applied as immune-enhanced chemo-embolization of liver tumors.
Assuntos
Embolização Terapêutica , Fibrinogênio/administração & dosagem , Neoplasias Hepáticas/terapia , Fígado/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Picibanil/administração & dosagem , Veia Porta/efeitos dos fármacos , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Movimento Celular/efeitos dos fármacos , Fígado/patologia , Macrófagos/imunologia , Masculino , Veia Porta/cirurgia , Ratos , Ratos Wistar , Receptores de Superfície Celular/metabolismoRESUMO
During oral infection, mucosal immunity assumes a predominant role. Here, we addressed the role of mast cells (MCs), which are mainly located in mucosa during oral infection with Toxoplasma gondii, using MC-deficient (W/W(v) ) mice. We show that in the absence of MCs the resistance of W/W(v) mice to oral infection was considerably reduced. W/W(v) mice uniformly succumbed within 15 days of infection after administration of cysts of the ME49 strain of T. gondii. The rapid lethality of T. gondii in W/W(v) mice correlated with a delayed Th1-cell response, since IFN-γ and IL-12 levels peaked in the later phase of the infection. In vitro, BM-derived MCs were able to recognize parasite lysate in a MyD88-dependent way, reaffirming the role of this TLR adapter in immune responses to T. gondii. The importance of MCs in vivo was confirmed when W/W(v) mice reconstituted with BM-derived MCs from control mice retrieved an early strong Th1-cell response and specially a significant IL-12 production. In conclusion, MCs play an important role for the development of a protective immune response during oral infection with T. gondii.
Assuntos
Imunidade nas Mucosas/imunologia , Mastócitos/imunologia , Toxoplasmose Animal/imunologia , Animais , Imunofluorescência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Th1/imunologia , Toxoplasma/imunologiaRESUMO
Infection with viral or bacterial pathogens has been linked with the development of multiple sclerosis (MS), while infection with helminth parasites has been associated protection against MS and other autoimmune diseases. Here we have used a murine model of MS, experimental autoimmune encephalomyelitis (EAE), to examine the effect of infection with the respiratory pathogen Bordetella pertussis infection on development of CNS inflammation. The data demonstrate that infection of mice with B. pertussis significantly attenuates the clinical course of EAE induced by active immunization or cell transfer. This was reflected in a significant reduction in VLA-4 and LFA-1 expression on T cells and infiltration of IL-17(+), IFN-γ(+) and IFN-γ(+)IL-17(+) CD4 T cells into the CNS. Infection with B. pertussis induced IL-10 production from dendritic cells in vitro and enhanced the frequency of IL-10-producing CD25(-)Foxp3(+/-) CD4(+) T cells in vivo. Furthermore, the suppressive effects of B. pertussis infection on EAE were lost in IL-10(-/-) mice. Our findings demonstrate that a bacterial infection of the respiratory tract can attenuate EAE by promoting production of the anti-inflammatory cytokine IL-10 that may suppress licensing of autoaggressive T cells in the lungs, thereby preventing their migration into the CNS.
Assuntos
Bordetella pertussis/patogenicidade , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/microbiologia , Interleucina-10/imunologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia , Animais , Mediadores da Inflamação/metabolismo , Interleucina-10/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/imunologia , Células Th17/imunologia , Células Th17/microbiologiaRESUMO
BACKGROUND: Th1/Th17 imbalance had been indicated to mediate several kinds of inflammatory diseases. We deduce that Th1/Th17 imbalance might also contribute to the pathogenesis of acute graft-versus-host disease (GVHD). This study is to investigate the relation between Th1/Th17 imbalance and acute GVHD. METHODS: We applied a murine GVHD model of C57BL/6 (H-2(b)) donor to BALB/c (H-2(d)) recipient by treating the recipients with low dose of halofuginone (HF), which is competent in selectively inhibiting Th17 differentiation and facilitating Th1 differentiation. Recipient mice were monitored for survival rate, body weight change, clinical symptoms and pathological evidence of acute GVHD. We also measured the proportions of Th1 and Th17 cells in circulation and expression levels of IFN-γ and IL-17A in tissues involved in GVHD. RESULTS: Firstly, we confirm the existence of Th1/Th17 imbalance in acute GVHD and Th1/Th17 imbalance positively correlates with severity of acute GVHD. Secondly, low dose of HF augments Th1/Th17 imbalance by driving the Th1/Th17 balance to a Th1-dominant reaction. Finally, augmented Th1/Th17 imbalance leads to aggravated systemic GVHD. An increased Th1-type reaction results in aggravated hepatic and intestinal GVHD, and inhibiting Th17 differentiation is sufficient to alleviate pulmonic impairment. CONCLUSION: Our study is indicative for a critical role of Th1/Th17 imbalance in the pathogenesis of murine GVHD.